HGF–MET Cascade, a Key Target for Inhibiting Cancer Metastasis: The Impact of NK4 Discovery on Cancer Biology and Therapeutics

Abstract

Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy.

Increased HGF Expression Induces Resistance to c-MET Tyrosine Kinase Inhibitors in Gastric Cancer

“…Although the inhibitory mechanisms of PHA-665752 are different for each cell type, PHA-665752 generally regulates morphogenic differentiation, cell survival, and motility by inhibiting p-AKT and p-ERK, and suppresses anchorage-independent growth of gastric, lung, and glioma cancer cell lines (4,6).…”

“…However, de novo resistance to these TKIs occurs because of c-MET amplification or HGF overexpression (20)(21)(22). c-MET overexpression contributes to tumor development via crosstalk between other receptors, such as EGFR, HER2, and HER3 (4,21). Moreover, overexpression of HGF stimulates c-MET activation which trans-phosphorylates other receptors (4).…”

“…c-MET overexpression contributes to tumor development via crosstalk between other receptors, such as EGFR, HER2, and HER3 (4,21). Moreover, overexpression of HGF stimulates c-MET activation which trans-phosphorylates other receptors (4). Accordingly, it is important to consider HGF status when therapeutic strategies targeting the HGF-c-MET axis are applied (23).…”

Immunoprofile of c-MET/PI3K signaling in human salivary gland tumors

“…[6][7][8][9][10] The binding of HGF to c-MET triggers the recruitment of the Grb2-SOS and Gab-1 proteins, leading to the activation of numerous signaling pathways, including Ras-ERK, PI3K/AKT, PLC, Shp-2, and Crk-2, which play important roles in cell proliferation, morphogenesis, and motility. 11 Although involved in important physiologic functions, overexpression of HGF and mutations in c-MET have been reported in some events related to malignant behavior including reduced cell-cell contact, activation of epithelial mesenchymal transition, increased tumor angiogenesis, and enhanced cellular survival. 11,12 Clinical trials examining the targeted inhibition of the HGF/c-MET circuitry have demonstrated improved outcomes for patients with different types of solid tumors.…”

“…11 Although involved in important physiologic functions, overexpression of HGF and mutations in c-MET have been reported in some events related to malignant behavior including reduced cell-cell contact, activation of epithelial mesenchymal transition, increased tumor angiogenesis, and enhanced cellular survival. 11,12 Clinical trials examining the targeted inhibition of the HGF/c-MET circuitry have demonstrated improved outcomes for patients with different types of solid tumors. 13,14 Very few studies have examined the role of the HGF/ c-MET pathway in SGTs.…”